Ketalization of hindered 20-keto steroids



Application February 25,4959 I molecule of water reactswith lthedioirolane inthei reac' tionfmix'turejto generate further ethylene glycol ana ro;

whieh' there is a li nllcage at the l 7n-position"toan oxygen atonifaridwhich are thereby 'sterically' hindered. More specifically the invention relates to the pro c'ess of forma tion of'compoundsofthe structuralfformulas V v and" wherein Ais hydrogenorfmethyl; X is an I group, Y is a hydrogen hydroxy o'rac'yloxy group H As the foregoing reaction sequence indicates, ethylene glycol a'cts as an intermediate catalyst; only a relatively small quantity of ethylene glycol need be added'and in practice it has been found that about 1-15% by' Weight of ethylene'glycol (based on the weight of thetotalmix;

tur'e) can be'us'efully. employed, The SteroidalZO-ketohe' R=CO reacts withthe" ethylene glycol-toflformth djesired'steroidal ketal an'd one molecule of vvaterl":"Ihis duties :a by-productone"molecule of a compound the formula The reaction iscarriedout Yin"a"ohe phase system; and

this distinguishes the procedure fro'm that'described'by Fernholz et" a1. (USA-Patents 2,356,154 and 2,378918) l Inthe Fernholz procedure ethylenedioxy derivatives' oi 'st'e'r'o'idal'ketones are l prepared by refluxing the ketone and'exce'ss ethylene glycol in -benzene,--toluene, or' di- 1 chloroethane; the water formed bythe condensation is' removed asan azeotrope and 'the up'perlayer of the dis+ tillate afterseparation is I returned to thereaction ture." This' method has been found'togive lowyields with sterically hindered -ketosteroids andis not 1 adaptable'to industrialapplications;- 'The present:procedure;

on the--'otherhand,- g'ives very high yields of the ZO e th- J yl enedioxyderivatives evenin the; presence of severe 'Amon'g-the dioxolanes which are useful for use in the procedure claimed are dioxolane' itself, its 2-methyl-2- and Z is a hydroxymethylene, acyloxymethylene or an ethylenedioxyniethylene' radical. The 'acyl groups referred to are derived from lower alkanoic acids such as acetic; propionicy butyricg valcric or caproic acid.

The foregoing compounds areconveniently prepared 3 in'goodyields by heating of the corresponding compound of the 'sarne' structural formula but wherein "X i's' defined as =0,with a dioxolane of the structural formula v I I V V 1 I H O n" wherein R andR" are-members of tl ie"cla ss' cons isting' ofih'ydrogem 'methyl and ethyl, in the presence of a cata Oils-.0

ethyl, 2;2-"dimethyl, and 2 ,2-diethyl derivatives. The preferred dioxolane is 2-methyl-2-ethyl-1 ,3-dioxolane because-the released "compound R 'COR is in this case butanone, which has a favorable boiling point Bum none isremoved from the system by distillation which isoperated at a very'high reflux ratio; thus permitting the butanone to 'be removed as it forms,-and--thereby favorably displacing the equilibrium. Since'butanone 118' GR is easyto control the progress of the reaction inaccordance withthe'temperature of the vapors at the top of the distillation column. A 'more' accurate-control of the state of the reaction, if desired,- can be achieved by measuring the volume of the distillate, reading the refractive index of the mixture ofhutanone and 2-meth"yl'-2-ethyl-1,3-dioxolane and making a comparison with'a curve of the refractive indices plotted for the system as a function of its butanone content. 2-methyl-2- ethyldioxolane has a refractiveindex u of 1.4085 and a butanone one oi-1.3777 and it is possible to establish at anytime-exactly how much 'butanonehas been remo'ved'from thesystem and in that -way to determine the rate of completion of the reaction, COlltI'OiOf this reaction isimportant because anexcessively long reacl tion time gives riseto polymerizatidmwhich hinders "the lytic quantity of ethylene glycoLfjThis ketaliz'ation is carried out in the presence of an' acid catalyst, preferably" sulfuric acid or" an aryl sulfonic'acid such as benzenesulfonic acid, toluene sulfonic acid, chlorobenzenesulfonic acid and naphthalenesulfonic .acid- The 'reactionapparentlyproceeds ma sequence ivihich eaiiihe depicted by the followingscheme, in whichR=COV represents the fiZO-keto steroid and Rf and jR f are, def

fined as vlhereina'bove. "I

lino-lo. I 0 QHOCHrCHlOHrl-R'IV'CO I i V crystallization of thefinal'product in such a way-that lower yields are obtained. -Completion of the reaction can also be determined by an infrared examination, and specifically by theelimination'of the barid'inthe' 5;9 micron-region.

When other dioxolanes areused shcb-dilueiitsljgas methyleycloheiiane,benzene; toluene, andxyl'ene can be employedse; as 'to' obtain optimal distillation conditiohsi Hoyvever; the" 2j-methyl- 2 ethyldioxolane,' which can be p f ed Fe 1 ,71

linkage from the-4-position to the 5 -position.

used with or without diluent, appears to be the preferred reagent.

The procedure also has great advantages over that o Dauben, Loken and .Ringold (J. Am. Chem. Soc., 76, 1359,; 19,54), which employs an exchange dioxolanation between a steroidal kctone and dialkyldioxolanes. While this methodis very useful for thev Selective ketalization of' steroidal keto groups exhibiting a low degree of steric hindrance it is not practical for the preparation of ethylenedioxy derivatives of ZO-keto steroids whichare strongly hindered, particularly by 17a-hydroxy or 16,17-epoxy substituents. Thus, l etalization in the case of 3 8-acetoxy- 16a,17aeepoxye5-pregnene2fl-one requires, 6 days under Dauben conditionfwhereas with the present procedure; which differs in the addition of a small amount of ethylene glycol to the reaction mixture, the reaction can be completed in about 12 hours.

Of special importance for the purpose of this invention are, the 17 substituted derivativesrgof progresterone. .These compounds contain, in addition to the sterically hindered keto group, the, sertically unhindered 3-keto group. Using thelDauben procedure mentioned hereinabove, the 3 -keto group can be readily converted to the S-ethlyenedioxy group with av concomitant shift of the unsaturated V h 15: sulting derivative o-f a Zip-cthylenedioxy-S,-pregnen-20.-one need; not be isolated; instead the ketalization of the 20; position can, beaccomplished by addition ofethylene glyc ol ,to the reactionmixturc and use of the refluxing procedure with removal of-the alkanoneRCOR.

More conveniently the ketalization of a. polyketone'can be, carried outby a continuous processsusing the. Sa e reaction mixture as employed for the ketalization of the ZO-ketone; in, sucha case, ,3rethylenedioxy-5-pregnen-20- one is presumably formed as an intermediate.

The present procedure provides ZO-ethylenedioxy steroids whichare valuable chemical intermediates. The desirability of temporarily blocking the ZO-keto function of;-a steroid is well recognized in the art, for instance, where Grignard reactions are to be carried out on the derivatives. A typical example is the prepartion of 6- methylated cortical steroids such as those described by G. B. Spero et al., J.A.C.S., 78: 6213, 1956. The method is also of special utility in the preparation of l6fi-methyl steroids. Thus, 3 3,17 -dihydroxy-16,3-methyl-5-pregnen- ZQ-one can beprepa red by a procedure developed by Dr. Luis Miramontes using as astarting material 3fl-hydroxyl6 -m ethy l- 5,l6-pregnadienr2Q-one which .is selectively epoxidized 'to the, 160:,170L 6P0Xld6 and then treated with hydrogen bromide.

The 20 ethylenedioxy 16B methyl 5 pregncne- 3fl, l7 ot-diql is a valuable intermediate. Thus on Oppenauer oxidation the A4-3-ketone isformed without significant D-homo rearrangement and on hydrolysis there is obtain the 16fi th l i hy xynr s s mn he ter can be acetylated to the 17-acetoxy derivative which is an, anti-estrogenic agent of low progestationalactivity.

am hyl 2 e hy ea iwsy 5 pr s me 3B,

head. In this apparatus a mixture of 69 g. of l7a-hydroxyprogesterone and 690 ml. of 2-methyl-2-ethyl-1,3'- dioxolane is distilled employing a reflux ratio of 1:40. When the temperature on top ofthe column has reached a constant level at 118 C., 270 mg. of p-toluene-sulfonic acid monohydrateare added and the heat is regulated to achieve maximum reflux in the column; 6 drops of distillate per minute are taken off. After 4 hours the ketalization' at the 3-carbonyl group. is completed andv the temperature at the top of the column. :remains constant at about 118 C Refractive .index readings of the distillate show. that 18 ml. of butanone .have been removed from the reaction (theory 18.75 ml.). At thispoint 11 ml. of ethylene glycol and approximately 50 mg. of the same acid catalyst are added to the. mixture which is heated again'as before except that only 2 drops per minute of distillate are collected. That -.thefketalization now progresses satisfactorily at the 20-keto function is indicated by a temperature drop' of the vapors at the top of the column. About 1 hour after the addition of ethylene glycol a temperature of 105 C. is observed. After about 12 hours, the temperature atthe top of the column has again reached l18 -C. Addition of a further 50 mg. portion of the monohydrate of p-t oluenesulfonic acid has no appreciable efiect on the reflux temperature. Refractive index readings show that a total of 36.5 ml. of butanone have been removed (theory 37.5). The reaction is thus essentially complete and the mixture is cooled in an ice water bath. Then 100 ml. Ma 5 aqueous solution of potassium carbonate are addedwith vigorous agitation. The aqueous layer is discarded and the dioxolane solution is subjected to direct steam distillation in the 7 presence of 1 g. of potassium carbonate. The residue in v bisethylenedioxy-S-pregnen-1704-01.

Example 2 In the apparatus described in Example; 1 -amixture;of

I 70 g. of 16u,17a-epoxy-4-pregnene-3,ZQ-dione, 690' :ml.

of 2-rnethyl-2-ethyl-1,3-dioxolane and 11 ml. of ethylene glycol is distilled employing a reflux ratio of 1:40. until thetemperature at the top of the colurnnhas reached 118 C. Then 300 mg. of p-toluenesulfonic acid catalyst are added and the mixture is maintained at reflux as in the preceding example, 2 drops of distillate being removed per minute. Purification as in'the preceding example yields 3,20-bisethylenedioxy-16a,17a-epoxy-S pregnene H melting at about 185-1865 C. The rotation of the Neutra can a so he u d s-au ut med a o he prep- 'a a on Qt l. .-dime l1-y '$te o ds hus. the; -pie n is subjected to the usual epoxidation procedure to form theS G -e Qxide which is then subjected to a Grignard rea t on n he ma n r u o hepr p a n of her 6-mcthyl steroids so as to yield the 6, ,6-dimethyl deriva- Example 1 The reaction is carried out in a 2-liter flask equipped,

with a packed, column. and a total reflux partial take-air chloroform solution e is .2 3 Reduction of thisbis;

hydrofuranrethanol solution containing sodium hydroxide for- 9 hoursyields 3,20-bisethylenedioxyri-pregnen-1'Zq-ol I identical with the-product as described in Example-1.

Example 3" Y I 15? reac n 9f the grs oi sa ma t iwsrfl d out with 3fi-ac'etoxy-l'6 ,17u-epoxy ipregnen-fll one. There is thus obtained the .3/3-acetoxy l6a,17a-epoxy-20rethylenedioxy-S-pregriene melting at about ISIS- 194 C. The

rotation of the chloroform solution ca is -3 8. In the same manner there'can be reacted the free 3B-hydroxy compound and the 3,6-butyroxyanalog. In each case the ethylenedioxy derivative is obtained in excellent yield.

Example 4 I I the rocedure of gauge 2', .35 of Salk-tuba I .5 droxy-S-pregnen-ZO-one are .substituted for ,the 70; g. of 1611,17u-epoxy-4-pregnenee3,20 =dlone ,toyield ZD-ethylenedioxy-.5 pregnene-3p ,l7 -diol meltingat about 187,5

189,2. C. .The rotation of 3 chloroform solution o 'is --45.5 A relativelysmall amount of steroidis usedin the reaction-mixture because of thelow solubility of the compound, .7 v u;

atotal reflux partial takeoff head,- a mixture off72 g."of 17a,2l dihydroxyprogesterone and 690ml. of 2-methyl-2- ethyl 1,3-dioxolane is distilleduntil the top of the-column. attains-a-constant temperatu ofiabout ll8 cil iThen 275 mg. of the monohydrate'foff. p-toluenesulfonic acid is added and the heat is regulated to achieve maximal added. and refluxingis continued at suchva rate thatlaboilt 2 drop's per'r'ninute of distillate-are collected. An additionalportionof 50mg. of p-toluenesulfonic acid monohydrate is added. and refluxing isicontinued for a dayafter b 5 constant reflux in the eolumn; 6"drops df distillate 'per minute being taken oif. Ater,..4 ho urs, 1 l ,ml, of, ethylene glycol and 50 mg. of the in'ono'h'ydrate "of p tdliiriesulfonic' acid are t i mp To a-solution of 10 g. of 16p-methyl-3B,l7a-dihydroxy- S-pregnen-ZO-one in 150 ml. of .2-methyl-2-ethyl-1,3-di-' oxolane are added 5 parts of ethylene glycol and then 0.2 g. of p-toluenesulfonic acid monohydrate. The mixture'is distilled in a flask equipped with a packed column and atotal'refluxpartial takebff head for4I-hou rs; A

high reflux ratio-is maintained and only 20 ml. 'of the mixture of 2'-methyl-2-ethyl-'l',3 dioxolane andbutanone are removed during this 'pe'riod of'reaction. Completeness of th ereaction is indicated by the following criteria:

(1) Complete ref lux in'"the column achieved byturningaofhthe take' ofi.stop 'cock does not change the vapor temperature at thetop of: the column, which remains '1.-(2) Refractive index readings of the total distillate collected"indicate-:tliat exactly '1 moleculanequivalent which the reaction mixture is cooled in an ice bath. 7

Then 100 ml. of a 5% aqueoussolution of potassium" carbonate are added with vigorous agitation. The organic layer is separated and subjected to direct steam distil:

lation in the presenceof l g., of potassiumcarbonate;

. The residue in the flask crystallizes and the crysta line mass is separated and suspended in a solution containing 5g. of potassium bicarbonate in methanol and filtered.

of butanoni: hasbeen removed.

show evidenc'e of the presence of-any 20-ketone.

. was reaction mixture? s cooled,' after which 2001-1111.

of a 5% potassium carbonate solution are added and the mixture is shakenvigorously. The lower layer is discarded and the upper layer is dried over anhydrous potassium carbonate and concentrated to a small volume under reduced pressure on the steam bath. Addition of methanol containing a' trace of pyridine causes the re- The cooled product is dissolved in dichloromethane containing calcium oxide and activated carbon in suspension. 7 filtered and concentrated. On addition of methanol and further concentration until the residualdichloromethane is eliminated there is obtained 3,20-bisethylenedioxy-5- pregnene-l7a,2l-diol, which, onrecrystallization from 'a mixture of acetone and ether, melts at about 216-218 C. The rotation of a chloroform solution ca is -36.

The reaction can be carried out under the same conditions with the l6l3-methyl derivative.

Example 6 i I In a flask equipped with a packed reflux'column and a total reflux partial take-off head, a mixture of' 18 g. of 17a-hydroxy-2l-acetoxy-4-pregnene-3,20-dione and 690 ml. of 2-methyl-2-ethyl-1,3-dioxolane is distilled un-' til the top of the column reaches a constant temperature of about 118 C. After addition of 275 mg. of themonohydrate of p-toluenesulfonic acid the heat is adjusted so I that maximum reflux is achieved. 6 drops of distillate per minute being taken off. After 4 hours a heavy crystalline slurry is obtained containing mainly the 3-monoketal, i.e. 3-ethylenedioxy-l7a-hydroxy 21-acetoxy 5- pregnen-ZO-one. Then 11 ml. of ethylene glycol and 50 mg. of the monohydrate of p-toluenesulfonic acidv are added and refluxing is continued so that about 2 drops of butanone are collected per minute. An additional portion of 50 mg. of p-toluenesulfonic acid monohydrate is added and refluxing is continued for 40 hours after which the reaction mixture is cooled in an ice bath. Then 100 ml. of a 5% aqueous solution of potassium carbonate are added with stirring. The organic layer is separated and subjected to direct steam distillation in thepresence' of 1 g. of sodium carbonate. Theresidue'inthevflask becomes crystalline and the precipitate is suspended in a' solution containing 5 g. of potassium bicarbonate in methanol and filtered. The cooled product is dissolved in dichloromethane containing calcium oxide in activated charcoal in suspension, filtered and concentrated. All dichloromethane is removed by continued concentration with occassional addition of methanol so as to yield 3,20- bisethylenedioxy-21-acetoxy-5-pregnen-l7a-ol which, .recrystallized from a mixture of acetone and ether. melts at about 216-2175 C. The solution is a -36".

s idual oil to crystallize. The crystals are collected on a filter and recrystallized from a mixture of dichloromethane and methanol containing a trace of'pyridine; V

and there is thus obtained l6B-methyl-ZO-ethylenedioxy- 5-pregnene-3B,l7b;-diol melting at about l76'-l78 C.

The rotation of the chloroform solution ca is 54.

What is claimed is:

l. The process for the preparation of a'member of the class consisting of the formulas wherein A is a member of the :class consisting of hydro- 1 gen and methyl, X is an --0CH --CH -O- group,

Y is a member of the class consistingof hydrogen, hy-

droxy and lower alkanoyloxy groups, and Z is a member rotation of a chloroform of thehclass consisting of fl-hydroxymethylene, fi-alkanoyloxymethylene and groups, which comprises refluxing the compound of at'the boilingf'of Z-methyPZ-ethyl-l,3 dioxolane; 51

.- 3 Infrared-measurements of the total solids d o' :not

same structural formula but wherein X is defined as with a compound of the formula @Hg-OI R l oHz-o R" wherein R and R" are members of the class consisting of hydrogen, methyl and ethyl in the presence of 1-15 by weight of ethylene glycol and an acid catalyst of the class consisting of sulfuric acid and arylsulfonic acids.

2-. The process according to claim 1, wherein R is a methyl and R is an ethyl group.

6 3. The process for the preparation of 3,2(l-bisethylene-r dioxy-S-pregnen-lh-ol which comprises refluxing 3- ethylenedioxy 17a hydroxy S-pregnen-ZO-one with 2- rnethyl-2-ethyl-1,3-dioxolane in the presence of 1-15% glycol and an acid catalyst of the class consisting of stil fuiflic acid and arylsulfor'iic acids;

5. The process for the preparation of 3,20-bisethylenedioxy-5-preg'nene-17:2;2I-di6l which comprises refluxing 3-ethylenedioxy-l7a,21 dihydrdziy 5-pregnen-20-one with 2-methyl-2-ethyl-l,-3-dioxolai1e in the presence of 1-15% by Weight of ethylene glycol and an acid catalyst of the class consisting of sulfuric acid and arylsulfonic acids.

6. The process for the preparation of 3,20-bisethylenedioxy-S-pregnene-17,2l-di01 which comprises refluxing %2 l-dihydroxyprogesterone with 2-methyl-2-ethyl-1,3- dioxolane in the presence of 115 by weight of ethylene glycol and an acid catalyst of the class consisting of'sulfuric acid anduarylsulfouic acids.

- V References Cited in the file ofthis patent V I I in UNl T ED STATES PATENTS UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 2,925,415 February 16, 1960 Bjarte Loken It is hereby certified that error appears in the-printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3 line 21' for "sertically read sterically line 54, for "l6B-ethyl" read log-methyl Signed and sealed this 16th day of Augustl960.

(SEAL) Attest:

KARL Ho AXLINE ROBERT (J. WATSON Attesting Ofiicer Commissioner of Patents 

1. THE PROCESS FOR THE PREPARATION OF A MEMBER OF THE CLASS CONSISTING OF THE FORMULAS 